Synthesis, docking and ADMET studies of novel chalcone triazoles for anti-cancer and anti-diabetic activity

Article abstract of DOI:10.1016/j.ejmech.2015.02.027

A series of novel chalcone-triazole derivatives were synthesized and screened for in vitro anticancer activity on the human cancer cell lines IMR32 (neuroblastoma), HepG2 (hepatoma) and MCF-7 (breast adenocarcinoma), DU-145 (prostate carcinoma), and A549

Full text of DOI:10.1016/j.ejmech.2015.02.027

Accepted Manuscript
Synthesis, docking and ADMET studies of novel chalcone triazoles for anti-cancer
and anti-diabetic activity
Yakaiah Chinthala, Sneha Thakur, Shalini Tirunagari, Srinivas Chinde, Anand kumar
Domatti, Niranjana Kumar Arigari, K.V.N.S. Srinivas, Sarfaraz Alam, J. Kotesh Kumar,
Feroz Khan, Ashok Tiwari, Paramjit Grover
PII:
S0223-5234(15)00123-3
10.1016/j.ejmech.2015.02.027
EJMECH 7709
DOI:
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 1 December 2014
Revised Date: 22 January 2015
Accepted Date: 18 February 2015
Please cite this article as: Y. Chinthala, S. Thakur, S. Tirunagari, S. Chinde, A.k. Domatti, N.K. Arigari,
K.V.N.S. Srinivas, S. Alam, J.K. Kumar, F. Khan, A. Tiwari, P. Grover, Synthesis, docking and ADMET
studies of novel chalcone triazoles for anti-cancer and anti-diabetic activity, European Journal of
Medicinal Chemistry (2015), doi: 10.1016/j.ejmech.2015.02.027.
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Graphical Abstract
Leave this area blank for abstract info.
Synthesis, docking and ADMET studies of novel chalcone triazoles for
anti-cancer and anti-diabetic activity
Yakaiah Chinthala, Sneha Thakur, Shalini Tirunagari, Srinivas Chinde, Anand kumar Domatti,
*
Niranjana Kumar Arigari, Srinivas K.V.N.S., Sarfaraz Alam, J. Kotesh Kumar , Feroz Khan, Ashok
Tiwari, Paramjit Grover

ACCEPTED MANUSCRIPT
Synthesis, docking and ADMET studies of novel chalcone triazoles for
anti-cancer and anti-diabetic activity
a
a
a
b
Yakaiah Chinthala , Sneha Thakur , Shalini Tirunagari , Srinivas Chinde , Anand kumar
c
a
a
d
Domatti , Niranjana Kumar Arigari , Srinivas K.V.N.S. , Sarfaraz Alam , J. Kotesh
a*
d
c
b
Kumar , Feroz Khan , Ashok Tiwari , Paramjit Grover
a
Natural Product Chemistry, CSIR-Central Institute of Medicinal and Aromatic Plants-
Research Centre, Boduppal, Hyderabad-500092, India
Toxicology Unit, Biology Division, CSIR-Indian Institute of Chemical Technology,
b
Hyderabad-500007, India.
Medicinal chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical
c
Technology, Hyderabad – 500007, India.
Metabolic and Structural Biology Department, CSIR-CIMAP, Lucknow-226015, UP
d
*
Corresponding: Telefax: +91-40-27202602; Email: koteshkumarj@yahoo.com
Abstract
A series of novel chalcone-triazole derivatives were synthesized and screened for in vitro
anticancer activity on the human cancer cell lines IMR32 (neuroblastoma), HepG2 (Human
hepatoma) and MCF-7 (Human breast adenocarcinoma), DU-145 (Human prostate carcinoma),
and A549 (Human Lung adenocarcinoma). Among the tested compounds, 4r showed the most
promising anticancer activity in all the cell lines whereas, compounds 4c (IC 65.86 µM), 4e
5
0
(
IC 66.28 µM), 4o (IC 35.81 µM), 4q (IC 50.82 µM) and 4s (IC 48.63 µM) showed better
50 50 50 50
activity than the standard doxorubicin (IC 69.33 µM) in A549 cell line alone. Rat intestinal α-
5
0
glucosidase inhibitory activity of the synthesized derivatives showed 4m (IC50 67.77 µM), 4p
IC50 74.94 in µM) and 4s (IC50 102.10 µM) as most active compared to others. The in silico
(
docking of synthesized derivatives 4a-4t with DNA topoisomerase IIα revealed the LibDock
score in the range of 71.2623 to 118.29 whereas, compounds 4h, 4m, 4p and 4s with docking
target α-glucosidase were in the range of 100.372 to 107.784.
Key words:
Chromanochalcones, 1,2,3-triazoles, Anticancer activity, α-Glucosidase inhibition, Molecular
docking.
1
. Introduction
The World Health Organization’s cancer agency warns that there will be 22 million new cases
of cancer every year within the next two decades. Report from the International Agency for
1

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Research on Cancer (IARC) estimated in 2012 that there were 14 million new cases but
predicted that the figure would jump significantly due to global ageing and the spread of cancers
to developing countries. Cancer, a diverse group of diseases characterized by uncontrolled
growth of abnormal cells and it is a fatal disease standing next to the cardiovascular disease in
terms of morbidity and mortality. Although the cancer research has led to a number of new and
effective solutions, the medicines used as treatments have clear limitations and unfortunately
cancer is projected as the primary cause of death in the future [1, 2]. Currently there is a huge
scientific and commercial interest in the discovery of potent, safe and selective anticancer drugs.
Diabetes Mellitus (DM) is also a growing health problem and according to WHO reports,
around 250 million people are currently living with diabetes and this number is expected to be
more than 366 million by 2030 [3]. Treatments of type 2 diabetes mellitus (T2DM) include
improvement of insulin sensitivity or reducing the rate of carbohydrate absorption from the
gastrointestinal tract. So far, the drugs used to treat T2DM have several side effects, especially
for those patients with liver and renal functional disorders [4]. α-glucosidase is a membrane-
bound enzyme at the epithelium of the small intestine and plays a key role in carbohydrate
digestion. Inhibition of α-glucosidase leads to the delay or reduction of increased postprandial
blood glucose levels. Thus, α-glucosidase inhibitors have been proposed as a potential
therapeutic target for drug discovery in the treatment of T2DM.
Chalcones (1,3-diaryl-2-propen-1-ones) constitute an important class of natural products
belonging to the flavonoid family, which display interesting biological activities including anti-
inflammatory [5], antibacterial [6], antioxidant [7], antimalarial [8] and anticancer [9]. Due to
their abundance in plants and ease of synthesis, this class of compounds has generated great
interest for possible therapeutic uses. They are also effective in vivo as cell proliferating
inhibitors, anti-tumor promoting and chemo preventing agents. Since a number of clinically
useful anticancer drugs have genotoxic effects due to interaction with the amino groups of
nucleic acids, chalcones may be devoid of this important side effect [10]. Despite the
comprehensive biological studies on chalcones, reports on their anti-diabetic activity are scarce
[11].
On the other hand, the 1,2,3-Triazoles have occupied an important role not only in organic
chemistry but also in medicinal chemistry due to their easy synthesis by click chemistry and
attractive features as well as numerous biological activities [12-14]. 1,2,3-triazoles are highly
2

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stable under acid/base hydrolysis and oxidative/reductive conditions, indicating its high aromatic
stabilization [15,16]. Moreover, these heterocyclic compounds have a high dipole moment and is
capable of forming hydrogen bonding, which could be favorable in the binding of biomolecular
targets [17]. 1,2,3-Triazole is one of the key structural units found in a large variety of bioactive
molecules as antifungal [18], antibacterial [19,20], antiallergic [21], antiHIV [22,23],
antitubercular [24,25] and antiinflammatory [26] agents. Several 1,2,3-triazole containing drug
molecules including tazobactum [27], carboxyamidotriazole [28] are now available in the
market. In recent year, researchers are increasingly focusing on their anticancer activity [29-37].
In the design of new drugs, the development of hybrid molecules through the combination of
different pharmacophores may lead to compounds with interesting biological profiles. These
agents show different mechanisms of action and a single molecule containing more than one
pharmacophore, each with different mode of action could be beneficial for the treatment. Hybrid
chalcones designed by chemically linking chalcones to other prominent anticancer scaffolds such
as pyrrol[2,1-c][1,4]benzodiazepines [38], benzopyran [39] have demonstrated synergistic or
additive pharmacological activities. By combining 1,2,3-triazole with other pharmacophores via.
click chemistry, potential bioactive compounds could be synthesized [40]. Thus, a series of
1
,2,3-triazoles hooked to β-lactam chalcones were designed and synthesized to yield novel
bioactive hybrids. The synthesized derivatives were screened for their anticancer and antidiabetic
properties in in vitro modes.
2
. Results and Discussion
2
.1. Chemistry
The synthetic strategy followed for the synthesis of different chalcone triazoles is outlined in
(
schem-1). A series of derivatives 4a-4t were synthesized in four steps. Chromans 2a, 2b were
prepared by reaction between isoprene and 2,4-dihydroxy Acetophenone. These intermediates
a, 2b were common to all molecules being synthesized. In the second step, 4-hydroxy
2
benzaldehyde was reacted with propargylbromide in presence of potassium carbonate at reflux
temperatures to obtain compound 3. In the third step, chromans were condensed with 4-(prop-2-
ynylony)-benzaldehyde 3 in the basic medium to give respective chalcones 3a and 3b. In the
final step, the chalcones 3a and 3b were further reacted with appropriately substituted aromatic
3

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azides by a click reaction to afford compounds 4a-4t. All the synthesized compounds were
1
13
1
characterized by H, C-NMR, Mass and IR spectroscopy. In the H-NMR the presence of
characteristic singlet at δ 2.73 (t, 2H, J = 6.7 Hz) for aliphatic proton provided evidence for
formation of 2a, 2b. Formation of the chalcones was characterized by a peculiar doublet for
olefin protons resonating at δ 7.47-7.50 ppm. Also, formation of chalcones-triazoles hybrids 4a-
4
t was confirmed by presence of a singlet for O-CH
2
protons resonating at δ 5.3 ppm. The IR
spectra of compounds 4a-4t showed the enolate protons and C=O stretching bands at 3460-3446
-1
-1
cm and 1735-1670 cm respectively.
Scheme 1: Synthesis of Chalcone 1,2,3-triazole derivatives
2
.2. Anticancer activity
Anti-cancer activity of the synthesized chalcone-triazole derivatives was evaluated in in vitro
mode using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay [41] on
the human cancer cell lines MCF-7 (Human breast adenocarcinoma), DU-145 (Human prostate
carcinoma), IMR-32 (neuroblastoma), A-549 (Human lung adenocarcinoma) and Hep-G2
(Human hematoma). The assay was dependent on the reduction of tetrazolium salt by the
mitochondrial dehydrogenase of viable cells to form a blue formazan product dissolved in
DMSO and measured at 570 nm. The results of cytotoxic activity were expressed as the IC50
(µM) and doxorubicin was used as positive control Table 1. The structural diversity in all the
derivatives was introduced by varying substitution at 3 position of the triazole ring while keeping
the chalcone-triazole moiety intact. As given in the Table 1, most of the compounds showed
moderate anticancer activity but, compound 4r significantly inhibited the growth of all the cell
lines when compared to its positional isomer 4o. Similarly, compounds 4c (IC 65.86 µM), 4e
5
0
(
IC 66.28 µM), 4o (IC 35.81 µM), 4q (IC 50.82 µM) and 4s (IC 48.63 µM) were behaved
50 50 50 50
better than the standard doxorubicin (IC50 37.65 µM) in only A549 cell lines.
2
.3. α-glucosidase inhibition
Rat Intestinal α-glucosidase inhibitory activity was determined as per earlier reported
methods [42,43]. Rat intestinal acetone powder in normal saline (100:1; w/v) was sonicated
4

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properly and the supernatant was used as a source of crude intestinal α-glucosidase after
centrifugation. In brief, 10 mL of test samples (5 mg/mL DMSO solution) were reconstituted in
1
00 mL of 100 mM phosphate buffer (pH 6.8) in 96-well microplate and incubated with 50 mL
yeast α-glucosidase (0.76 U/Ml in same buffer) or crude intestinal α-glucosidase for 5 min before
0 mL substrate (5 mM, p-nitrophenyl-α-D-glucopyranoside prepared in same buffer) was
added. Release of p-nitrophenol was measured at 405 nm spectrophotometrically (SpectraMAx
5
3
84
Plus , Molecular Devices Corporation, Sunnyvale, CA, USA) 5 min after incubation with
substrate. Individual blanks for test samples were prepared to correct back-ground absorbance
where substrate was replaced with 50 µL of buffer. Control sample contained 10 µL DMSO in
place of test samples. Acarbose was taken as standard reference for α-glucosidase inhibition. All
the samples were studied in triplicate. Percentage of enzyme inhibition was calculated as (1-
B/A) x 100 where A represents absorbance of control without test samples, and B represents
absorbance in presence of test samples. All the tests were run in duplicate. The IC values were
5
0
calculated applying suitable regression analysis from the mean inhibitory values. As shown in
Table 1, amongst all the synthesized derivatives, compounds 4m (IC 67.77 µM), 4p (IC 74.94
5
0
50
in µM) and 4s (IC 102.10 µM) have shown better α-glucosidase enzyme inhibitory activity.
5
0
Comparing the α-glucosidase inhibitory activity of compounds it is inferred that the presence of
aliphatic chain length up to five carbons attached to the triazole moiety may be ideal to generate
activity.
Table 1: Anticancer and α-glucosidase inhibitory activity of compound 4a-4t.
2
.4. Molecular docking and in silico pharmacology studies
Protein–ligand docking studies
The docking study of chalcone derivatives 4a-4t with DNA topoisomerase IIα (PDB:
1
7
ZXM) revealed the high docking score (LibDock) and binding affinities [44], in the range of
1.2623 to 118.29, as compared to Doxorubicine 125.857 (Fig. 1, Table 2 and Fig S1 (in
Supplementary)). Similarly, chalcone triazoles, which were active in vitro, have shown docking
scores in the range of 100.372 to 107.784 (Fig. 2, Table 3 and Fig. S2 (in Supplementary)) when
docked with α-Glucosidase (PDB: 2QMJ). These results indicate that most of the compounds
5

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bound within the binding site pocket of doxorubicin and similar binding pattern with binding site
amino acid residues. Few compounds bound at different binding site of DNA topoisomerase IIα.
In case of docking with α-glucosidase, compound 4m showed the similar binding pattern as
acarbose, a known antidiabetic drug. On the other hand compounds 4d, 4h, and 4s showed
diverse binding site locations. The significant binding affinity on respective targets infers that
these compounds are very active and can be potential leads against cancer and diabetes.
These results indicate that the compounds are bound well within the binding site pocket
of doxorubicin and almost similar binding pattern were identified. In case of docking with α-
glucosidase, all the studied compounds showed similar docking results quantitatively as
compared to in vitro activity. Detailed analysis of the results showing various interactions, such
as hydrogen bonds, atomic charge interactions and Pi interactions between the surrounding
residues and the ligand were mapped. These interactions are displayed with 2D diagram and
represented by different colors like pink indicates electrostatic interaction; purple indicates
covalent bond and green indicates van der–Waals molecular interaction. Solvent accessibility of
the ligand atom and the amino acid residues are shown in light blue shading surrounding the
atom or residue. High shading indicates more exposure to solvent. The significant docking score
on the respective targets infers that these compounds are promiscuous and can be potential leads
against cancer and diabetes.
Fig. 1 Structural model of DNA topoisomerase II α (PDB: 1ZXM) with doxorubicin binding
site (sphere); (B) Binding site and binding pattern of candidate compound along with
control.
Fig. 2 Structural model of α-glucosidase (PDB: 2QMJ) with Acarbose binding site (sphere). (B)
Binding site and binding pattern of candidate compound along with control.
Table 2: Details of LibDock score, hydrogen bonds, Pi interactions and active site pocket
residues revealed
through molecular docking of Chalcone derivatives and
Doxorubicin on DNA Topoisomerase IIα (PDB: 1ZXM).
Table 3: Details of LibDock score, hydrogen bonds, Pi interactions and active site pocket
residues revealed through molecular docking of Chalcone derivatives and Acarbose
on α-glucosidase (PDB: 2QMJ)
6

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Bioavailability and drug likeness screening
Different chemical descriptors for the pharmacokinetics properties were calculated to
check the compliance of studied compound with the standard range. For this the aqueous
solubility, blood–brain barrier penetration, cytochrome P450 2D6 binding, hepatotoxicity,
intestinal absorption, and plasma protein binding were calculated [45]. The calculation of these
chemical properties was intended as the first step toward analyzing the novel chemical entities,
in order to check the failure of lead candidates which may cause toxicity or metabolized by the
body in to an inactive form or one unable to cross the intestinal membranes. The
pharmacokinetic profiles of all the compounds under investigation were predicted by means of
six pre-calculated ADMET models and result provided in Table S1 in supplementary. The
aqueous solubility prediction (defined in water at 25°C) indicated that all the compounds are
soluble in water. The compounds are found to be non-inhibitors of cytochrome P450 2D6
(CYP2D6). The CYP2D6 enzyme is one of the important enzymes involved in drug metabolism.
During ADME screening, the predictive hepatotoxicity was observed for some of the candidate
compounds in comparison to acarbose (non-toxic) and doxorubicin (toxic). The candidate
compounds are found to be highly bound with plasma protein binding in comparison to acarbose
and doxorubicin.
Prediction of toxic effect
The safety of the compounds is absolutely crucial for a successful drug. To grab this, the
different toxicity risk screening such as skin irritancy, ocular irritancy, mutagenicity, aerobic
biodegradability and developmental toxicity potential was checked for all the compounds (Table
S2, in supplementary). All the compounds are found to be non-mutagenic and either mild or no
irritancy (Ocular & Skin) when compared to doxorubicin which is mutagenic and acarbose
which shows severe ocular irritancy. The dose dependent toxicity such as Rat Oral LD , Rat
5
0
Inhalational LC50, Carcinogenic Potency TD50, Rat Maximum Tolerated Dose feed, Daphnia
EC (mg/l), Rat Chronic LOAEL along with effective concentration extent are provided for each
50
compound in Table S2. These results will help to set dose-ranges for animal assays.
3
. Conclusion
7

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Synthesis of a series of novel hybrid molecules consisting of biologically important
pharmacophores Chromano chalcones tagged with substituted 1,2,3-triazoles showed potential
anticancer and antidiabetic activity. Among the synthesized compounds, 4r showed the most
promising anticancer activity in all the cell lines and about nine compounds out twenty
derivatives were active against A-549 cell line. Compounds 4m, 4p and 4s showed promising α-
glucosidase inhibitory activity. The in silico docking with DNA topoisomerase IIα and α-
glucosidase targets and toxicity studies revealed high binding affinities and within toxicity limits
required in the drug discovery procedure.
4
.
Experimental
4
.1. Chemistry
Melting points of all the compounds were recorded on Casia-Siamia (VMP-AM) melting point
apparatus and uncorrected. IR spectra were recorded on a Perkin–Elmer FT-IR 240-C
spectrometer using KBr optics. NMR spectra were recorded on Burker Avance 300 MHz in
CDCl and DMSO-d using TMS as internal standard. Electron impact (EI) and chemical
3
6
ionization mass spectra were recorded on a VG Micro mass model 7070H instrument. All the
reactions were monitored on silica gel percolated TLC plates of Merck and spots were visualized
with UV light. Silica gel (100-200 mesh) used for column chromatography was procured from
Merck.
4
.1.1. Synthesis of 1-(5-hydroxy-2, 2-dimethyl-3, 4-dihydro-2H-chromen-6-yl) ethanone (2a)
and 1-(7-hydroxy-2, 2-dimethyl-3, 4-dihydroxy-2H-chromen-6-yl) ethanone (2b) General
procedure
1
-(5-hydroxy-2, 2-dimethyl-3, 4-dihydro-2H-chromen-6-yl) ethanone (2a) and 1-(7-
hydroxy-2,2-dimethyl-3,4-dihydroxy-2H-chromen-6-yl)ethanone(2b) to a stirred solution of
Amberlyst-15 (6.2 gm) and 1-(2,4-dihydroxyphenyl)-ethanone 1 (4.56 gm, 30 mmol) in THF (10
°
ml) at 65-70 C, isoprene (3.2 ml, 4.7 mmol) in heptane (10 ml) was added drop wise over a
period of 2h. The reaction mixture was filtered and washed with hot acetone (2 × 50 ml) and
separated by column chromatography using hexane/ethyl acetate (8:2 and 6:4) as eluent to afford
2
1
2
a (2.8 g, 43%) and 2b (0.95 g, 15%) in pure state.
-(5-hydroxy-2, 2-dimethylchroman-6-yl) ethanone 2a White solid, m.p. 70 C, IR (KBr): 3429,
°
-1 1
967, 2925, 2855, 1629, 1489, 1427, 1363, 1263, 1154, 1067, 614 cm ; H-NMR (CDCl 200
3
,
8

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MHz) δ (ppm): 13.11(s, 1H, chelated OH), 7.49 (d, 1H, J = 8.9 Hz,), 6.33 (d, 1H, J = 8.9 Hz),
2
1
3
.68 (t, 2H, J = 6.7 Hz), 2.54 (s, 3H, COCH ), 1.80 (t, 2H, J = 6.7 Hz), 1.34 (s, 6H).
3
°
-(7-hydroxy-2, 2-dimethylchroman-6-yl) ethanone 2b White solid, m.p. 118 C, IR (KBr):
-1
1
3
429, 2927, 2856, 1642, 1494,1365, 1281, 1159, 1056, 811, 655 cm ; H-NMR (CDCl , 200
MHz) δ (ppm): 12.32 (s, 1H, chelated OH), 7.43 (s,1H), 6.31 (s,1H), 2.73 (t, 2H, J = 6.7 Hz),
2
.53 (s, 3H, COCH
.1.2. Procedure for propargylation for synthesis of 4-(prop-2-ynylony) benzaldehyde
-hydroxy benzaldehyde (1.0 mol) along with 1.5 mol of potassium carbonate was taken
3
), 1.82 (t, 2H, J = 6.7 Hz), 1.34 (s, 6H).
4
4
in dimethyl formamide (DMF) and added to this solution of propargyl bromide (1.5 mol) in
DMF. Reaction mixture was stirred (reflux) to afford crude 4-(prop-2-ynylony) benzaldehyde.
This crude compound was column chromatographed over silica gel (100-200 mesh) and eluted
with 15 % ethyl acetate in n-hexane to obtain pure compound 3.
1
4
3
1
4
-(prop-2-ynylony) benzaldehyde 3 White solid, yield: 92%; m.p.76-78 °C, H-NMR (CDCl
3
,
00 MHz) δ (ppm): 1.25 (s, 2H), 2.57 (s, 1H), 4.29-4.79 (s, 2H), 7.09-7.11 (d, 1H), 7.86-7.88 (d,
H), 9.99 (s, CHO).
.1.3. Procedure for the synthesis of chalcones 3b-(E)-1-(7-hydroxy-2, 2-dimethylchroman-6-
yl)-3-(4-(prop-2-ynyloxy) phenyl) prop-2-en-1-one
To a solution of chromanes 2a/2b (5 g, 22.7 mol) was added KOH (3.63 g, 1 mol) and a
solution of 3 (1.9 g, 1.5 mol) in ethanol (5 mL), and the mixture was stirred at 35-40 °C for 6h.
After dilution with water (100 mL) and acidification with cold diluted hydrochloric acid (25 mL)
the resulting solid filtered off, washed with water and recrystallized form petroleum ether to give
yellow needles 3a/3b.
(E)-1-(7-hydroxy-2,2-dimethylchroman-6-yl)-3-(4-(prop-2-ynyloxy)phenyl)prop-2-en-1-one
(3a) Yellow solid, yield: 85%; m.p.124-125 °C; IR (KBr) 3450, 2976, 2934, 1630, 1561, 1363,
-
1 1
1
2
9
216, 1170, 1021 cm ; H NMR (CDCl , 300 MHz) δ (ppm): 1.365 (s, 6H), 1.812-1.846 (t, 2H),
3
.55-2.565 (t, 1H), 2.704-2.740 (t, 2H), 4.74-4.74 (d, 2H, J = 2.510 Hz), 6.369-6.392 (d, 1H, J =
.035 Hz), 7.00-7.03 (d, 2H, J = 9.035 Hz), 7.466-7.50 (d, 1H, J = 15.53 Hz), 7.60-7.62 (d, 2H, J
=
9.288 Hz), 7.68-7.70 (d, 1H, J = 9.288 Hz), 7.82-7.86 (d, 1H, J = 15.560 Hz), 13.92 (s, 1H).
1
3
C NMR (75 Hz, CDCl
3
) δ (ppm): 16.37, 26.74, 31.87, 55.86, 75.81, 76.02, 76.71, 78.01,
1
1
06.14, 109.34, 112.86, 115.33, 118.66, 128.46, 128.54, 130.17, 143.41, 159.45, 160.77, 164.11,
91.81. ESI-MS (m/z) 363 (M+ 1) observed for C23
9
22 4
H O .

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(E)-1-(5-hydroxy-2,2-dimethylchroman-6-yl)-3-(4-(prop-2-ynyloxy)phenyl)prop-2-en-1-one
(3b) Yellow solid, yield: 85%; m.p.130-132 °C; IR (KBr) 3416, 3231, 2923, 1638, 1553, 1365,
-
1 1
1
2
2
1
7
1
4
224, 1149, 1027 cm ; H NMR (CDCl , 300 MHz) δ (ppm): 1.36 (s, 6H), 1.82-1.86 (t, 2H),
3
.55-2.57 (t, 1H), 2.75-2.79 (t, 2H), 4.73-4.74 (d, 2H, J = 2.510 Hz), 6.35 (s, 1H), 7.00-7.02 (d,
H, J = 9.035 Hz), 7.44-7.48 (d, 1H, J = 15.81 Hz), 7.61-7.63 (d, 3H, J = 9.53 Hz), 7.80-7.84 (d,
1
3
3
H, J = 15.560 Hz), 13.06 (s, 1H). C NMR (75 Hz, CDCl ) δ (ppm): 21.81, 26.99, 32.78, 55.86,
5.95, 76.05, 76.73, 78.01, 104.89, 112.68, 114.23, 115.33, 118.60, 128.50, 130.21, 131.06,
43.56, 159.48, 161.41, 164.13, 191.68. ESI-MS (m/z) 363 (M+ 1) observed for C H O .
2
3
22
4
.1.4. Synthesis of Synthesis of Chalcones-Triazole derivatives (4a-4t)
Intermediate, (E)-1-(7-hydroxy-2,2-dimethylchroman-6-yl)-3-(4-(prop-2-ynyloxy)
phenyl)-prop-2-en-1-one, 3a/3b (1.0 mmol) was dissolved in dry THF (10 mL) and catalytic
amount of copper iodide was added. To this, substituted aromatic and aliphatic azides (1.0
mmol), in dry THF, were added slowly while stirring at room temperature under nitrogen
atmosphere for 12 h. Later, the solvent was removed under reduced pressure and the residue was
diluted with distilled water and extracted thrice with dichloromethane. The combined organic
layers were dried over anhydrous Na
2 4
SO and concentrated to get the product. The crude product
was purified by column chromatography with ethyl acetate in hexane.
4
.1.5.(E)-3-(4-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-1-(7-hydroxy-2,2-
dimethylchroman-6-yl)prop-2-en-1-one (4a) Yellow solid, yield: 92%, m.p.171-172 °C, IR
-
1 1
(
KBr) 3446, 2927, 2866, 1603, 1508,1385, 1247, 1172, 1021, 811, 653 cm
;
H-NMR (CDCl
00 MHz) δ (ppm): 1.381 (s, 6H), 1.821-1.866 (t, 2H), 2.714-2.756 (t, 2H), 5.35 (s, 2H), 6.380-
.410 (d, 1H, J = 9.042 Hz), 7.060-7.086 (d, 2H, J = 8.65 Hz), 7.468-7.535 (m, 3H), 7.618-7.647
3
,
3
6
(d, 2H, J = 8.655 Hz), 7.687-7.697 (d, 2H, J = 3.20 Hz) , 7.71 -7.72 (d, 1H, J = 23.20 Hz) , 7.82-
1
3
7
1
1
.87 (d, 1H, J = 15.447 Hz), 8.068 (s, 1H) ,13.92 (s, 1H). C-NMR (CDCl 75 Hz) δ (ppm):
3,
6.36, 26.74, 29.70, 31.86, 62.00, 75.81, 109.15, 109.34, 112.84, 115.22, 118.62, 120.91, 121.76,
28.41, 128.46, 130.01, 130.32, 134.82, 135.38, 143.36, 144.73, 160.05, 160.79, 164.11. ESI-
MS (m/z) 518 (M+ 2) observed for C H ClN O .
2
9
26
3
4
4
.1.6. (E)-3-(4-((1-(4-bromophenyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-1-(7-hydroxy-2,2-
dimethylchroman-6-yl)prop-2-en-1-one (4b) Yellow solid, yield: 85%, m.p.199-200 °C, IR
-1 1
(
3
KBr) 3447, 2927, 1636, 1559, 1348, 1247, 1144, 1023, 823, 620 cm ; H-NMR (CDCl , 300
1
0

ACCEPTED MANUSCRIPT
MHz) δ (ppm): 1.369 (s, 6H), 1.818-1.85 (t, 2H), 2.7-2.74 (t, 2H), 5.35 (s, 2H), 6.37-6.39 (d, 1H,
J = 9.035 Hz), 7.05-7.079 (d, 2H, J = 9.28 Hz), 7.47-7.512 (d, 1H, J = 15.309 Hz), 7.62-7.63 (d,
1
H, J = 4.26 Hz), 7.6-7.64 (d, 1H, J = 2.00 Hz), 7.65-7.67 (m, 3H), 7.68-7.70 (d, 2H, J = 9.28
Hz), 7.8-7.86 (d, 1H, J = 15.309 Hz), 8.06 (s, 1H), 13.921 (s, 1H). ESI-MS (m/z) 561 (M+ 1)
observed for C H BrN O .
2
9
26
3
4
4
.1.7.
(E)-1-(7-hydroxy-2,2-dimethylchroman-6-yl)-3-(4-((1-(2-methyl-3-nitrophenyl)-1H-
1
,2,3-triazol-4-yl)methoxy)phenyl)prop-2-en-1-one (4c) Yellow solid, yield: 80%, m.p.174-176
°
-1 1
C, IR (KBr) 3448, 2923, 2853, 1632, 1368, 1223, 1174, 1039 cm ; H-NMR (CDCl , 300 MHz)
3
δ (ppm): 1.36 (s, 6H), 1.83-1.86 (t, 2H), 2.313 (s, 3H), 2.76-2.80 (t, 2H), 5.39 (s, 2H), 6.36 (s,
1
2
1
4
1
1
H), 7.07-7.09 (d, 2H, J = 9.03 Hz), 7.46-7.50 (d, 1H, J = 15.56 Hz), 7.52-7.56 (t, 1H), 7.6 (s,
H), 7.62-7.66 (d, 2H, J = 9.03 Hz), 7.8-7.86 (d, 1H, J = 15.3 Hz), 7.89 (s, 1H), 8.04-8.07 (d,
H, J = 9.78 Hz), 13.05 (s, 1H). ESI-MS (m/z) 541 (M+ 1) observed for C H N O .
3
0
28
4
6
.1.8.(E)-1-(7-hydroxy-2,2-dimethylchroman-6-yl)-3-(4-((1-(4-methoxy-2-nitrophenyl)-1H-
,2,3-triazol-4-yl)methoxy)phenyl)prop-2-en-1-one (4d) Yellow solid, yield: 83%, m.p.197-
0
-1 1
98 C, IR (KBr): 3446, 2927, 2866, 1603, 1508, 1385, 1247, 1172, 1021, 811, 653 cm ; H-
, 300 MHz): δ 1.368 (s, 6H), 1.817-1.851 (t, 2H), 2.708-2.743 (t, 2H), 3.874 (s,
H), 5.347 (s, 2H), 6.372-6.395 (d, 1H, J = 9.035 Hz), 7.016 -7.039 (d, 2H, J = 9.285 Hz), 7.063
7.086 (d, 2H, J = 9.035 Hz), 7.471 -7.510 (d, 1H, J =15.550 Hz),7.617 -7.626 (d, 1H, J = 3.514
NMR (CDCl
3
3
-
Hz), 7.640 -7.648 (d, 2H, J = 3.54 Hz), 7.687 -7.709 (d, 1H, J = 9.035 Hz), 7.829-7.868 (d, 1H,
J = 15.560 Hz), 7.988 (s, 1H), 13.925 (s, 1H). ESI-MS (m/z) 557 (M+ 1) observed for
30 28 4 7.
C H N O
4
.1.9. (E)-3-(4-((1-(4-acetylphenyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-1-(7-hydroxy-2,2-
°
dimethylchroman-6-yl)prop-2-en-1-one (4e) Yellow solid, yield: 93%, m.p.179-180 C, IR
-1
1
(
KBr) 3426, 2930, 1631, 1512,1364, 1223, 1175, 1045 cm ; H-NMR (CDCl
3
, 300 MHz) δ
(ppm): 1.36 (s, 6H), 1.81-1.85 (t, 2H), 2.66 (s, 3H), 2.70-2.74 (t, 2H), 5.36 (s, 2H), 6.34-6.39 (d,
1
2
1
H, J = 9.03 Hz), 7.06-7.08 (d, 2H, J = 9.28 Hz), 7.47-7.51(d, 1H, J = 15.30 Hz), 7.62-7.64 (d,
H, J = 9.03 Hz), 7.68-7.70 (d, 1H, J = 9.28 Hz), 7.82-7.86 (d, 1H, J = 15.30 Hz), 7.88-7.90 (d,
H, J = 9.03 Hz), 8.21 (s, 1H), 8.15-8.16 (d, 2H, J = 5.01 Hz), 13.91 (s, 1H). ESI-MS (m/z) 524
29 3 5
(M+ 1) observed for C31H N O .
4
.1.10. (E)-3-(4-((1-(2-ethylphenyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-1-(7-hydroxy-2,2-
°
dimethylchroman-6-yl)prop-2-en-1-one (4f) Yellow solid, yield: 70%, m.p.120-122 C, IR
1
1

ACCEPTED MANUSCRIPT
-1
(
KBr) 3446, 2927, 2866, 1603, 1508, 1385, 1247, 1172, 1021, 811, 653 cm
.
ESI-MS (m/z) 510
(
M+ 1) observed for C H N O .
3
1
31
3
4
4
.1.11.(E)-3-(4-((1-(3-bromo-4-methylphenyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-1-(7-
hydroxy-2,2-dimethylchroman-6-yl)prop-2-en-1-one (4g) Yellow solid, yield: 90%, m.p. 151-
-
1
52 °C, IR (KBr) 3479, 2924, 2854, 1626, 1506, 1365, 1223, 1109, 1042, 871, 796, 694, 600 cm
1
1
;
3
H-NMR (CDCl , 300 MHz) δ (ppm): 1.368 (s, 6H), 1.816-1.850 (t, 2H), 2.467 (s, 3H), 2.707-
2
.743 (t, 2H), 5.347 (s, 2H), 6.372-6.394 (d, 1H, J = 9.035 Hz), 7.054-7.077 (d, 2H, J = 9.035
Hz), 7.376-7.399 (d, 1H, J = 8.282 Hz), 7.471-7.510 (d, 1H, J = 15.560 Hz), 7.591-7.597 (d, 1H,
J = 2.259 Hz), 7.612-7.619 (d, 1H, J = 2.761 Hz), 7.641(s, 1H), 7.685-7.707 (d, 1H, J = 9.035
Hz), 7.826-7.865 (d, 1H, J = 15.560 Hz), 7.949-7.955 (d, 1H, J = 2.510 Hz), 8.039(s, 1H),
1
3 4
3.952 (s, 1H). ESI-MS (m/z) 575 (M+ 1) observed for C30H28BrN O .
4
.1.12. (E)-3-(4-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-1-(5-hydroxy-2,2-
°
dimethylchroman-6-yl)prop-2-en-1-one (4h) Yellow solid, yield: 92%, m.p.196-197 C, IR
-
1
1
(
KBr) 3415, 2924, 2850, 1637, 1560, 1349, 1115, 1012 cm ; H-NMR (CDCl
ppm): 1.381 (s, 6H), 1.821-1.866 (t, 2H), 2.714-2.756 (t, 2H), 5.355 (s, 2H), 6.380- 6.410 (d,
H, J = 9.042 Hz) ,7.060-7.086 (d, 2H, J = 8.655 Hz), 7.468-7.535 (m, 3H) 7.618-7.647 (d, 2H, J
8.655 Hz), 7.687-7.697 (d, 2H, J = 3.202 Hz) , 7.717 -7.728 (d, 1H, J = 23.202 Hz) , 7.824-
3
, 300 MHz) δ
(
1
=
1
3
7
1
1
.876 (d, 1H, J = 15.447 Hz), 8.068 (s, 1H), 13.920 (s, 1H); C-NMR (75 Hz, CDCl ) δ (ppm):
3
6.36, 26.74, 29.70, 31.86, 62.00, 75.81,109.15, 109.34, 112.84, 115.22, 118.62, 120.91, 121.76,
28.41, 128.46, 130.01, 130.32, 134.82, 135.38, 143.36, 144.73, 160.05, 160.79, 164.11. ESI-
MS (m/z) 517 (M+ 1) observed for C29
3 4
H26ClN O .
4
.1.13. (E)-3-(4-((1-(4-bromophenyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-1-(5-hydroxy-2,2-
°
dimethylchroman-6-yl)prop-2-en-1-one (4i) Yellow solid, yield: 85%, m.p.142-143 C; IR
-
1 1
(
(
(
(
(
4
3
KBr) 3414, 2925, 1636, 1559, 1350, 1247, 1145, 1023, 825 cm ; H-NMR (CDCl , 300 MHz) δ
ppm): 1.367 (s, 6H), 1.82-1.86 (t, 2H), 2.76-2.79 (t, 2H), 5.35 (s, 2H), 6.36 (s, 1H) ,7.06-7.08
d, 2H, J = 9.035 Hz), 7.45-7.49 (d, 1H, J = 5.5 Hz), 7.61-7.63 (d, 2H, J = 5.77 Hz), 7.65-7.66
d, 5H, J = 5.019 Hz), 7.8-7.85 (d, 1H, J = 15.309 Hz), 8.06 (s, 1H), 13.06 (s, 1H). ESI-MS
m/z) 561 (M+ 1) observed for C H BrN O .
2
9
26
3
4
.1.14.
(E)-1-(5-hydroxy-2,2-dimethylchroman-6-yl)-3-(4-((1-(2-methyl-3-nitrophenyl)-1H-
1
,2,3 triazol-4-yl)methoxy)phenyl)prop-2-en-1-one (4j) Yellow solid, yield: 82%, m.p. 172-173
°
-1 1
3
C; IR (KBr) 3414, 2929, 2859, 1637, 1565,1346, 1252, 1149, 1034 cm ; H-NMR (CDCl , 300
1
2

ACCEPTED MANUSCRIPT
MHz) δ (ppm): 1.37 (s, 6H), 1.82-1.85 (t, 2H), 2.31 (s, 3H) 2.71-2.75 (t, 2H), 5.38 (s, 2H), 6.37-
6
7
9
.39 (d, 1H, J = 9.03 Hz), 7.062-7.08 (d, 2H, J = 9.03 Hz),7.48-7.52 (d, 1H, J = 15.81 Hz), 7.54-
.56 (d, 1H, J = 8.53 Hz), 7.63 (s, 1H), 7.62-7.63 (d, 1H, J = 3.51 Hz), 7.69-7.71 (d, 2H, J =
.03 Hz), 7.82-7.9 (m, 2H), 8.05-8.07 (d, 1H, J = 7.78 Hz), 13.91 (s, 1H). ESI-MS (m/z) 541
(
M+ 1) observed for C H N O .
30 28 4 6
4
1
1
.1.15.(E)-1-(5-hydroxy-2,2-dimethylchroman-6-yl)-3-(4-((1-(4-methoxy-2-nitrophenyl)-1H-
,2,3-triazol-4-yl)methoxy)phenyl)prop-2-en-1-one (4k) Yellow solid, yield: 80%, m.p. 192-
°
-1 1
93 C, IR (KBr) 3416, 2932, 2860, 1637, 1541, 1509,1359, 1239, 1150, 1039 cm ; H-NMR
, 300 MHz) δ (ppm): 1.368 (s, 6H), 1.817-1.851 (t, 2H), 2.708-2.743 (t, 2H), 3.874 (s,
H), 5.347 (s, 2H), 6.372-6.395 ( d, 1H, J = 9.035 Hz), 7.016 -7.039 (d, 2H, J = 9.285 Hz), 7.063
(CDCl
3
3
-
7.086 (d, 2H, J = 9.035 Hz), 7.471 -7.510 (d, 1H, J = 15.550 Hz), 7.617 -7.626 (d, 1H, J =
.514 Hz), 7.640 -7.648 (d, 2H, J = 3.54 Hz), 7.687 -7.709 (d, 1H, J = 9.035 Hz), 7.829-7.868
d, 1H, J = 15.560 Hz), 7.988 (s, 1H), 13.925 (s, 1H). ESI-MS (m/z) 557 (M+ 1) observed for
3
(
30 28 4 7
C H N O .
4
.1.16. (E)-3-(4-((1-(4-acetylphenyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-1-(5-hydroxy-2,2-
°
dimethylchroman-6-yl)prop-2-en-1-one (4l) Yellow solid, yield: 85%, m.p. 189-190 C; IR
-1 1
(
KBr) 3415, 2927, 2856, 1679, 1636, 1509, 1361, 1246, 1150, 1015 cm ; H-NMR (CDCl , 300
3
MHz) δ (ppm): 1.36 (s, 6H), 1.81-1.85 (t, 2H), 2.66 (s, 3H), 2.70-2.74 (t, 2H), 5.36 (s, 2H), 6.34-
6
7
7
.39 (d, 1H, J = 9.03 Hz), 7.06-7.08 (d, 2H, J = 9.28 Hz), 7.47-7.51 (d, 1H, J = 15.30 Hz), 7.62-
.64 (d, 2H, J = 9.03 Hz), 7.68-7.70 (d, 1H, J = 9.28 Hz), 7.82-7.86 (d, 1H, J = 15.30 Hz), 7.88-
.90 (d, 1H, J = 9.03 Hz), 8.21 (s, 1H), 8.15-8.16 (d, 2H, J = 5.01 Hz), 13.91 (s, 1H). ESI-MS
(
m/z) 524 (M+ 1) observed for C H N O .
31 29 3 5
4
.1.17. (E)-3-(4-((1-(2-ethylphenyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-1-(5-hydroxy-2,2-
°
1
dimethylchroman-6-yl)prop-2-en-1-one (4m) Yellow solid, yield: 70%, m.p. 99-100 C; H-
NMR (CDCl , 300 MHz) δ (ppm): 1.09-1.13 (t, 3H), 1.36 (s, 6H), 1.83-1.86 (t, 2H), 2.47-2.53
3
(q, 2H), 2.76-2.80 (t, 2H), 5.37 (s, 2H), 6.37 (s, 1H), 7.08-7.10 (d, 2H, J = 9.035 Hz), 7.29-7.37
(m, 2H), 7.41-7.43 (d, 1H, J = 7.278 Hz), 7.46-7.50 (m, 2H), 7.62-7.63 (d, 2H, J = 4.51Hz), 7.66
(s, 1H), 7.82-7.86 (d, 2H, J = 16.313 Hz), 13.07 (s, 1H). ESI-MS (m/z) 510 (M+ 1) observed for
31 31 3 4
C H N O .
4
.1.18.(E)-3-(4-((1-(3-bromo-4-methylphenyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-1-(5-
hydroxy-2,2-dimethylchroman-6-yl)prop-2-en-1-one (4n) Yellow solid, yield: 90%, m.p. 200-
1
3

ACCEPTED MANUSCRIPT
°
-1 1
2
02 C; IR (KBr) 3415, 2933, 1636, 1554, 1358, 1297, 1149, 1010 cm ; H-NMR (CDCl
MHz) δ (ppm): 1.368 (s, 6H), 1.816-1.850 (t, 2H), 2.467 (s, 3H), 2.707-2.743 (t, 2H), 5.347 (s,
H), 6.372-6.394 (d, 1H, J = 9.035 Hz), 7.054-7.077 (d, 2H, J = 9.035 Hz), 7.376-7.399 (d, 1H, J
8.282 Hz), 7.471-7.510 (d, 1H, J = 15.560 Hz), 7.591-7.597 (d, 1H, J = 2.259 Hz), 7.612-7.619
d, 1H, J = 2.761 Hz), 7.641 (s, 1H), 7.685-7.707 (d, 1H, J = 9.035 Hz), 7.826-7.865 (d, 1H, J =
5.560 Hz), 7.949-7.955 (d, 1H, J = 2.510 Hz), 8.039 (s, 1H), 13.952 (s, 1H). ESI-MS (m/z) 575
M+ 1) observed for C H BrN O .
3
, 300
2
=
(
1
(
3
0
28
3
4
4
4
3
.1.19. (E)-1-(7-hydroxy-2,2-dimethylchroman-6-yl)-3-(4-((1-(4-nitrobenzyl)-1H-1,2,3-triazol-
°
-yl)methoxy)phenyl)prop-2-en-1-one (4o) Yellow solid, yield: 75%, m.p. 156-157 C; IR (KBr)
-1
1
450, 2930, 1630, 1518, 1350, 1221, 1111, 1048, 833 cm ; H-NMR (CDCl , 300 MHz) δ
3
(ppm): 1.368 (s, 6H), 1.817-1.852 (t, 2H), 2.707-2.743 (t, 2H), 5.27 (s, 2H), 5.67 (s, 2H), 6.372-
6
7
.394 (d, 1H, J = 9.035 Hz), 7.054-7.077 (d, 2H, J = 9.035 Hz), 7.41-7.43 (d, 1H, J = 9.035 Hz),
.46-7.510 (d, 1H, J = 15.30 Hz), 7.591-7.597 (d, 1H, J = 9.035 Hz), 7.63 (s, 1H), 7.685-7.707
(d, 2H, J = 9.28 Hz), 7.826-7.865 (d, 2H, J = 15.81 Hz), 8.23-8.26 (d, 2H, J = 9.035 Hz), 13.952
(
s, 1H). ESI-MS (m/z) 541 (M+ 1) observed for C H N O .
3
0
28
4
6
4
.1.20.
(E)-1-(7-hydroxy-2,2-dimethylchroman-6-yl)-3-(4-((1-pentyl-1H-1,2,3-triazol-4-
°
yl)methoxy)phenyl)prop-2-en-1-one (4p) Yellow solid, yield: 85%, m.p. 104-105 C; IR (KBr)
-
1 1
3
0
4
7
449, 2932, 1622, 1554, 1365, 1224, 1108 cm ; H-NMR (CDCl , 300 MHz) δ (ppm): 0.883-
3
.919 (t, 3H), 1.36 (s, 4H), 1.57 (s, 6H), 1.81-1.85 (t, 2H), 1.88-1.963 (m, 2H), 2.70-2.74 (t, 2H),
.34-4.38 (t, 2H), 5.27 (s, 2H), 6.37-6.39 (d, 1H, J = 9.03 Hz), 7.02-7.05 (d, 2H, J = 9.03 Hz),
.46-7.50 (d, 1H, J = 15.56 Hz), 7.60-7.61 (d, 2H, J = 4.26 Hz), 7.62 (s, 1H) 7.68- 7.70 (d, 1H,
J = 9.28 Hz), 7.82-7.86 (d, 1H, J = 15.30 Hz ), 13.93 (s, 1H). ESI-MS (m/z) 476 (M+ 1)
observed for C H N O .
2
8
33
3
4
4
.1.21.
(E)-1-(7-hydroxy-2,2-dimethylchroman-6-yl)-3-(4-((1-octyl-1H-1,2,3-triazol-4-
°
yl)methoxy)phenyl)prop-2-en-1-one (4q) Yellow solid, yield: 75%, m.p. 101-102 C; IR (KBr):
-
1 1
3
3
4
7
7
3
417, 2928, 2856, 1630, 1367, 1221, 1047 cm ; H-NMR (CDCl , 300 MHz) δ (ppm): 0.873 (s,
H), 1.251-1.322 (m, 10H), 1.367 (s, 6H), 1.59 (s, 2H), 1.817-1.85 (t, 2H), 2.70-2.74 (t, 2H),
.34-4.36 (t, 2H), 5.27 (s, 2H), 6.37-6.39 (d, 1H, J = 9.03 Hz), 7.02-7.04 (d, 2H, J = 9.03 Hz),
.46-7.50 (d, 1H, J = 15.56 Hz), 7.60-7.62 (m, 3H, J = 9.53 Hz), 7.68-7.70 (d, 1H, J = 9.28 Hz),
.82-7.86 (d, 1H, J = 15.56 Hz), 13.93 (s, 1H). ESI-MS (m/z) 518 (M+ 1) observed for
31 39 3 4
C H N O .
1
4

ACCEPTED MANUSCRIPT
4
4
3
.1.22. (E)-1-(5-hydroxy-2,2-dimethylchroman-6-yl)-3-(4-((1-(4-nitrobenzyl)-1H-1,2,3-triazol-
°
-yl)methoxy)phenyl)prop-2-en-1-one (4r) Yellow solid, yield: 75%, m.p. 148-150 C; IR (KBr)
-1
1
415, 2930, 2852, 1636, 1512, 1352, 1299, 1150, 836, 796, 678 cm ; H-NMR (CDCl , 300
3
MHz) δ (ppm): 1.368 (s, 6H), 1.817-1.852 (t, 2H), 2.707-2.743 (t, 2H), 5.27 (s, 2H), 5.67 (s, 2H),
6
2
.37 (s, 1H), 7.054-7.077 (d, 2H, J = 9.28 Hz), 7.41-7.43 (m, 2H, J = 13.80 Hz), 7.46-7.510 (d,
H, J = 13.30 Hz), 7.61-7.64 (d, 2H, J = 10.54 Hz), 7.826-7.865 (d, 2H, J = 15.51 Hz), 8.23-8.26
(
d, 2H, J = 9.285 Hz), 13.952 (s, 1H). ESI-MS (m/z) 541 (M+ 1) observed for C H N O .
30 28 4 6
4
.1.23.
(E)-1-(5-hydroxy-2,2-dimethylchroman-6-yl)-3-(4-((1-pentyl-1H-1,2,3-triazol-4-
°
yl)methoxy)phenyl)prop-2-en-1-one (4s) Yellow solid, yield: 85%, m.p. 110-111 C; IR (KBr)
-1
1
3
415, 2927, 2859, 1638, 1555, 1360, 1247, 1149, 1050 cm ; H-NMR (CDCl , 300 MHz) δ
3
(
ppm): 0.883-0.919 (t, 3H), 1.25-1.30 (m, 4H), 1.36 (s, 6H), 1.82-1.86 (t, 2H), 1.90-1.96 (m, 2H),
.76-2.80 (t, 2H), 4.34-4.38 (t, 2H), 5.27 (s, 2H), 6.37 (s, 1H), 7.054-7.077 (d, 2H, J = 9.035
Hz), 7.26 (s, 1H), 7.41-7.43 (d, 1H, J = 15.56 Hz), 7.62-7.63 (d, 2H, J = 7.027 Hz), 7.826-7.865
d, 1H, J = 15.56 Hz), 13.07 (s, 1H). ESI-MS (m/z) 476 (M+ 1) observed for C28
.1.24. (E)-1-(5-hydroxy-2,2-dimethylchroman-6-yl)-3-(4-((1-octyl-1H-1,2,3-triazol-4-
yl)methoxy)phenyl)prop-2-en-1-one (4t) Yellow solid, yield: 86%, m.p. 88-89 C; IR (KBr)
2
(
33 3 4
H N O .
4
°
-
1 1
3
0
2
7
415, 2924, 2855, 1634, 1554, 1362, 1245, 1150 cm ; H-NMR (CDCl , 300 MHz) δ (ppm):
3
.874 (s, 3H), 1.25-1.32 (m, 10H, J = 7.278 Hz), 1.368 (s, 6H), 1.59 (s, 2H), 1.816-1.850 (t, 2H),
.467 (s, 3H), 2.707-2.743 (t, 2H), 5.347 (s, 2H), 6.372-6.394 (d, 1H, J = 9.035 Hz), 7.054-
.077 (d, 2H, J = 9.035 Hz), 7.376-7.399 (d, 1H, J = 8.28 Hz), 7.471-7.510 (d, 1H, J = 15.56
Hz), 7.591-7.597 (d, 1H, J = 2.25 Hz), 7.612-7.619 (d, 1H, J = 2.761 Hz), 7.641 (s, 1H), 7.61-
7
1
.62 (d, 2H, J = 2.8 Hz), 7.63-7.64 (d, 2H, J = 2.259 Hz), 7.81-7.85 (d, 1H, J = 15.56 Hz),
3.072 (s, 1H). ESI-MS (m/z) 518 (M+ 1) observed for C H N O .
3
1
39
3
4
Supplementary
Tables S1 and S2 consisting of in silico parameters of oral bioavailability, drug likeness
properties, toxicity risk assessment and various NMR and mass spectra of all the synthesized
derivatives were provided in supplementary.
1
5

ACCEPTED MANUSCRIPT
Acknowledgments
Authors thank Director, CSIR-CIMAP, Lucknow and Scientist-In-Charge, CSIR-
CIMAP-Research Centre, Hyderabad, India for their constant encouragement and support.
Author Yakaiah thanks CSIR-New Delhi for granting Senior Research Fellowship.
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Figures & Legends:
Fig. 1 Structural model of topoisomerase II α (PDB: 1ZXM, chain A and B) showing binding
pattern of candidate compound along with control (yellow colour).
2
0

ACCEPTED MANUSCRIPT
Fig. 2 Structural model of α-glucosidase (PDB: 2QMJ) showing binding pattern of candidate
compound along with control (red colour).
Scheme 1: Synthesis of Chalcone 1,2,3 tiazole derivatives
Tables:
Table 1: Anticancer and α-glucosidase inhibitory activity of compound 4a-4t.
Table 2: Details of Docking energy, active site pocket residues and hydrogen bonds revealed
through molecular docking of Chalcone derivatives and Doxorubicin on Topoisomerase
II (PDB: 1ZXM)
Table 3: Details of binding affinity, active site pocket residues and hydrogen bonds revealed
through molecular docking of Chalcone derivatives and Acarbose on α-Glucosidase
(PDB: 2QMJ)
2
1

ACCEPTED MANUSCRIPT
Table 1: Anticancer and α-glucosidase inhibitory activity of compound 4a-4t.
Compound α-glucosidase Anticancer activity
inhibition
MCF-7
DU-145
IC50 in µM
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
1MR-32
A-549
Hep G2
IC50 in µM
NA
NA
108.89
NA
IC50 in µM
NA
NA
NA
NA
NA
NA
NA
127.90
NA
NA
NA
NA
67.77
NA
NA
74.94
NA
NA
102.10
NA
IC in µM
IC in µM
IC in µM
50
50
50
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
NA
NA
176.03
NA
181.54
NA
NA
NA
NA
145.09
73.08
171.39
NA
NA
NA
NA
NA
17.11
190.61
NA
92.13
69.42
NA
NA
NA
NA
NA
NA
117.19
73.53
132.08
89.55
NA
NA
107.82
NA
7.09
17.34
NA
NA
NA
75.46
79.99
65.86
99.48
66.28
137.35
125.37
NA
NA
114.73
116.79
102.16
135.86
115.46
119.96
91.39
67.77
110.41
108.89
95.81
127.46
69.90
9.82
128.59
NA
NA
149.27
111.60
NA
35.81
91.29
50.82
69.88
48.63
NA
NA
NA
29.88
NA
NA
s
t
74.11
NA
Acarbose
Doxorubicin
NA-Not Active
23.87
NA
NA
NA
NA
2.63
17.67
44.40
69.33
1.05
Table 2: Details of LibDock score, hydrogen bonds, Pi interactions and active site pocket
residues revealed through molecular docking of Chalcone derivatives and Doxorubicin on DNA
Topoisomerase IIα (PDB: 1ZXM).
Com LibDo -H
Pi
Active site pocket residues
poun ck sco bond
interact
ion
d
re
4
4
4
4
4
4
a
114.67 NO
8
NO
ILE88, ASN91, ALA92, ASN95, ARG98, ILE118, ASN120,
ILE125, PRO126, HIS130, VAL137, ILE141, PHE142, SER148,
SER149, THR215, ILE217
b
c
d
e
f
112.13 TYR
ILE125 ILE88, ASN91, ALA92, ASN95, ARG98, ILE118, ASN120,
ILE125, PRO126, HIS130, VAL137, ILE141, PHE142,
SER149,ALA167, THR215, ILE217
5
186
71.262 LYS
NO
NO
NO
NO
ASN91, ASP94, ASN95, ARG98, ILE125, PRO126, VAL137,
ILE141, PHE142, THR147, SER148, SER149, ASN150, GLU155,
LYS157, THR159, GLY161, GLY164, ALA167, LYS168
ILE88, ASN91, ALA92, ASN95, ARG98, ILE118, TRP119,
ASN120, ILE125, PRO126, HIS130, VAL137, ILE141, PHE142,
SER148, SER149, ALA167, LYS168, THR215, ILE217
ILE88, ASN91, ALA92, ASN95, ARG98, ILE118, ASN120,
ILE125, PRO126, HIS130, VAL137, ILE141, PHE142, SER149.
THR215, ILE217
ASN91, ALA92, ASP94, ASN95, ARG98, ASN120, LYS123,
GLY124, ILE125, PRO126, HIS130, VAL137, ILE141, PHE142,
THR147, SER148, SER149, GLY161, GLY164, LYS168,
THR215, ILE217
3
157 (2)
76.324 NO
2
101.44 NO
5
112.69 NO
3

ACCEPTED MANUSCRIPT
4
4
4
g
h
i
95.239 ARG
98
LYS157 ILE88, ASN91, ALA92, ASN95, ARG98, ASN120, LYS123,
ILE125, PRO126, VAL137, ILE141, PHE142, SER148, SER149,
GLU155, LYS157, ALA167, THR215, ILE217
6
99.424 NO
6
ARG98 ASN91, ASP94, ASN95, ARG98, LYS123, ILE125, PRO126,
(2)
ILE141, THR147, SER148, SER149, ASN150, LYS157, GLY161,
ARG162, GLY164, ALA167, LYS168
103.28 NO
1
ARG98 ILE88, ASN91, ALA92, ASP94, ASN95, GLN97, ARG98,
(2) ASN120, ILE125, PRO126, ILE141, PHE142, THR147, SER148,
LYS123 SER149, LYS157, THR159, ALA167, LYS168, THR215, ILE217
LYS157
4
4
4
4
4
4
j
75.655 ARG
ARG98 ILE88, ASN91, ALA92, ASN95, GLN97, ARG98, ASN120,
LYS123, ILE125, PRO126, VAL137, ILE141, PHE142, THR147,
SER148, SER149, GLU155, LYS157, ALA167, THR215, ILE217
9
98
k
l
73.454 NO
NO
ILE88, ASN91, ALA92, ASN95, ARG98, ILE118, ASN120,
ILE125, PRO126, VAL137, ILE141, PHE142, SER149, THR215,
ILE217
104.48 HIS
ILE125 ILE88, ASN91, ALA92, ASN95, ARG98, ILE118, TRP119,
ASN120, ILE125, PRO126, HIS130, VAL137, LEU140, ILE141,
PHE142, SER149, THR215, ILE217
LYS157 ASN91, ALA92, ASN95, ARG98, ASN120, ILE125, VAL137,
ILE141, PHE142, THR147, SER148, SER149, GLU155, LYS157,
THR215
1
30
m
n
o
79.411 NO
7
111.32 SER
ARG98 ASN91, ARG98, LYS123, GLY124, ILE125, PRO126, ILE141,
3
183
(3)
PHE142, THR147, SER148, SER149, GLY164, TYR165,
ILE141 GLY166, ALA167, LYS168
91.525 ARG
NO
ASN91, ARG98, LYS123, ILE125, PRO126, VAL137, ILE141,
2
98 (3)
TYR
SER148, SER149, ASN150, LYS157, GLY161, GLY164,
TYR165, GLY166, ALA167, LYS168
1
65
LYS
68
1
4
4
P
q
100.69 NO
NO
NO
ILE88, ASN91, ALA92, ASP94, ASN95, ARG98, ILE118,
TRP119, ASN120, ILE125, PRO126, VAL137, ILE141, PHE142,
SER148, SER149, THR215, ILE217
ASN91, ASP94, ARG98, LYS123, GLY124, ILE125, PRO126,
VAL137, ILE141, PHE142, THR147, SER148, SER149, GLY161,
ARG162, ASN163, GLY164, TYR165, GLY166, ALA167,
LYS168
118.29 NO
4
4
4
r
s
t
95.601 ASN
PHE142 ASN91, ALA92, ASN95, ARG98, ASN120, LYS123, GLY124,
ILE125, PRO126, VAL137, ILE141, PHE142, SER148, SER149,
GLU155, LYS157, LYS168, THR215
ILE125 ILE88, ASN91, ALA92, ASN95, ARG98, ILE118, TRP119,
ASN120, ILE125, PRO126, HIS130, VAL137, ILE141, PHE142,
SER149, THR215, CYS216, ILE217
ILE141 ASN91, GLN97, ARG98, LYS123, ILE125, PRO126, VAL137,
ILE141, PHE142, THR147, SER148, SER149, GLU155, LYS157,
THR159, GLY164, TYR165, GLY166, ALA167, LYS168
8
120
99.869 TYR
186
9
109.87 NO
Doxo 125.85 ASN
NO
ASN91, ALA92, ASP94, ASN95, ARG98, ASN120, ILE125,
PRO126, ILE141, PHE142, THR147, SER148, SER149, GLY164,
ALA167, LYS168, THR215
rubici
n
7
91
LYS
1
68 (2)

ACCEPTED MANUSCRIPT
Table 3: Details of LibDock score, hydrogen bonds, Pi interactions and active site pocket
residues revealed through molecular docking of Chalcone derivatives and Acarbose on α-
glucosidase (PDB: 2QMJ)
Com LibDoc
poun k score
d
-H bond Pi
interact
ion
Active site pocket residues
4
h
100.372 ARG
26
ASP542
104.681 ARG
26 (2)
PHE450 ASP203, TYR299, ASP327, ILE328, ARG334, ILE364,
GLU404, TRP406, TRP441, ASP443, MET444, PHE450,
LYS480, ARG526, ASP542, PHE575, HIS600
TRP406 ASP203, THR204, THR205, PRO206, ASP327, ILE328,
HIS600 ILE364, TRP406, TRP441, ASP443, MET444, PHE450,
ARG526, TRP539, ASP54, THR544, PHE575, ALA576,
LEU577, HIS600, TYR605
5
4
m
5
4
4
p
s
106.353 ASN
07
ARG
26
107.784 ARG
26
TRP406 THR205, ASN207, ASN209, TYR299, ASP327, ILE328,
ILE364, TRP406, TRP441, ASP443, MET444, ARG526,
TRP539, ASP542, THR544, PHE575, ALA576, LEU577,
ARG598, HIS600, TYR605
TRP406 THR205, TYR299, ASP327, ILE364, TRP406, TRP441,
ASP443, ARG526, TRP539, ASP542, THR544, ASP571,
PHE575, ALA576, LEU577, ARG598, HIS600, TYR605
2
5
5
Acar
bose
123.536 THR
NO
ASP203, THR205, ASN207, TYR299, ASP327, ILE328,
ILE364, TRP406, TRP441, ASP443, MET444, ARG526,
TRP539, ASP542, THR544, PHE575, ALA576, HIS600
205
ASN
2
07
ASP
3
27 (2)
ARG
5
26
ASP
42 (2)
5

ACCEPTED MANUSCRIPT
Fig. 1 Structural model of DNA topoisomerase II α (PDB: 1ZXM) with doxorubicin binding site
(sphere); (B) Binding site and binding pattern of candidate compound along with control.
Fig. 2 Structural model of α-glucosidase (PDB: 2QMJ) with Acarbose binding site (sphere). (B)
Binding site and binding pattern of candidate compound along with control.
1

ACCEPTED MANUSCRIPT
Scheme 1: Synthesis of Chalcone 1,2,3 triazole derivatives
2

ACCEPTED MANUSCRIPT
ꢀ
ꢀ
ꢀ
ꢀ
Dimethyl chromano chalcones were tagged with substituted 1,2,3-triazoles.
Chalcone-triazoles were synthesized and screened for in vitro anticancer activity.
Compounds showed good α-glucosidase inhibition.
Molecular docking, bioavailability and toxicity risk assessment were mapped.

ACCEPTED MANUSCRIPT
SUPPORTING INFORMATION
Synthesis, docking and ADMET studies of novel chalcone triazoles for
anti-cancer and anti-diabetic activity
a
a
a
b
Yakaiah Chinthala , Sneha Thakur , Shalini Tirunagari , Srinivas Chinde , Anand
c
a
a
d
kumar Domatti , Niranjana Kumar Arigari , Srinivas K.V.N.S. , Sarfaraz Alam , J.
a*
d
c
b
Kotesh Kumar , Feroz Khan , Ashok Tiwari , Paramjit Grover
a
Natural Product Chemistry, CSIR-Central Institute of Medicinal and Aromatic Plants-
Research Centre, Boduppal, Hyderabad-500092, India
Toxicology Unit, Biology Division, CSIR-Indian Institute of Chemical Technology,
b
Hyderabad-500007, India.
Medicinal chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical
c
Technology, Hyderabad – 500007, India.
Metabolic and Structural Biology Department, CSIR-CIMAP, Lucknow-226015, UP
d
*
Corresponding: Telefax: +91-40-27202602; Email: koteshkumarj@yahoo.com
Abstract
A series of novel chalcone-triazole derivatives were synthesized and screened for in vitro
anticancer activity on the human cancer cell lines IMR32 (neuroblastoma), HepG2
(Human hepatoma) and MCF-7 (Human breast adenocarcinoma), DU-145 (Human
prostate carcinoma), and A549 (Human Lung adenocarcinoma). Among the tested
compounds, 4r showed the most promising anticancer activity in all the cell lines
whereas, compounds 4c (IC 65.86 µM), 4e (IC 66.28 µM), 4o (IC 35.81 µM), 4q
5
0
50
50
(
IC50 50.82 µM) and 4s (IC50 48.63 µM) showed better activity than the standard
doxorubicin (IC50 69.33 µM) in A549 cell line alone. Rat intestinal α-glucosidase
inhibitory activity of the synthesized derivatives showed 4m (IC 67.77 µM), 4p (IC
50
5
0
7
4.94 in µM) and 4s (IC 102.10 µM) as most active compared to others. The in silico
50
docking of synthesized derivatives 4a-4t with DNA topoisomerase IIα revealed the
LibDock score in the range of 71.2623 to 118.29 whereas, compounds 4h, 4m, 4p and 4s
with docking target α-glucosidase were in the range of 100.372 to 107.784.
Key words:
Chromanochalcones, 1,2,3-triazoles, Anticancer activity, α-Glucosidase inhibition,
Molecular docking.
1